1. Field of the Invention
The invention relates to the use of specific water soluble β-(1,3) glucans as active agents for combating the formation of wrinkles in the skin as well as epithelial tissue diseases.
2. Description of the Prior Art
The formation of wrinkles caused by increasing age is induced through the degradation of different macro molecules such as for example elastin and collagen, which are responsible for the elastases. Many inflammatory skin diseases, such as for example psoriasis or UV erythema, can also be causatively be linked to an increased concentration of serine proteases, such as e.g. elastase in the upper skin areas (see R. Voegeli et al 1996. in Cosm. Toil. 111, 51).
The formation of wrinkles in the skin is normally not counteracted by means of physiological active principles, but by means of cosmetic agents. Many so-called “anti-aging products” contain liposomes loaded with water or aqueous active agents, which through the fat layer of the skin are reaching the epidermis, where they gradually dissolve and through continuous water release compensate the skin recesses and regulate the moisture content of the skin. However, this effect is no combat against the causes, but only has a so-called “repairing effect”, which only lasts for a short period of time.
In contrast to this pure cosmetic use, cytostatic active agents are e.g. used for the abatement of psoriasis, such as selenium sulfide, cadmium sulfide, zinc pyrithion or corticosteroid, the medical effect of which resides e.g. in a reduction of the mitose activity in the basal membrane. However, because of the known side effects these substances should not be used over extended periods of time. Further it is possible to alleviate, but not heal, psoriasis by means of antiseptic active agents, such as for example selenium oxide, salicylic acid, pyrithione derivatives, hexachlorophene or quaternary ammonium compounds or by means of cell dissolving and fat removing active substances such as for example benzoy peroxide or tar extracts.
Ulcers manifest as lesions or sores in the skin or mucous membranes resulting from a successive disintegration of surface epithelial tissues that make them distinctive from wounds. The ulcer might be superficial, but in most cases the ulcer extends into deeper layers forming a crater surrounded by defined edges, and is typically very painful. The etiologies of the different ulcers are different, where faulty blood circulation, infection, nerve damage, trauma or cancers might be inductive. Examples of ulcers are diabetic ulcers, plantar ulcers, peptic ulcers, decubitus ulcers, venous ulcers, ischemic ulcers, cancerous ulcers, aphthous ulcers, sublingual ulcers, and atonic ulcers. Whereas, diabetic ulcers are known to have a very complicated etiology, many of the other ulcers have single or defined causes, wherein infections, faulty blood circulation and cancer would be directly involved in the formation of apthous, decubitus, and cancerous ulcers, respectively. An ulcer is considered chronic when it does not heal in a timely fashion.
Diabetic ulcers represent a serious problem because of their delayed or deficient healing often leading to chronic wounds that become high risk for major complications including infections and amputations. The latter is substantiated by the fact that diabetic patients have the highest amputation rate of any type of chronic wound, in some prospective studies as much as 20% of the patients, adding to another 20% experiencing failed healing (see Margolis et al 1999, Diabetes Care 22:692-695). Whereas, the etiology of most wounds and ulcers is identified, that supports the development of preventive care and wound treatment methods and drugs, this is not the case with diabetic ulcers where numerous factors contributing to the chronic wound development are involved. This includes predisposition for atherosclerosis and neuropathy, renal failure, microvascular disease, oedema, preponderance for infections, impaired leukocyte function, increased destruction of growth factors due to increased amounts of matrix metalloproteinases in the wound fluid, and hyperglycemia. In addition, it has been demonstrated that a macrophage dysfunction contributes to the disturbed wound healing process in diabetic ulcers (see Zykova et al. 2000, Diabetes 49:1451-1458). Several approaches to enhance the wound healing process in diabetic ulcers have been employed including the use of transplants and growth factors, but so far with scarcely any success (see Greenhalgh 2003, Clin Plast Surg 30: 37-45).
The use of specific polysaccharides as agents against the skin aging is also known from prior art. It has for example been proposed in U.S. Pat. No. 5,223,491 to use a carboxymethylated β-1,3 glucan, which has been extracted from the yeast fungi Saccharomyces cerevisiae, for topical use. However, the glucan is insoluble in water and can therefore only be formulated with large difficulties.
In the European patent application EP-A1 0463540 (Taito) the use of glucans against viruses is described. According to the teachings in the two papers DE-A1 3744345 (Lomapharm) and EP-B1 0175667 (Larm) glucans are only suited for stimulation of the activity of macrophages. The pharmaceutical effect of different glucans is further known from the two European patent applications EP-A1 045338 (Debat) and EP-A1 0561408 (Kaken). The object of the European patent EP-B1 0500718 (Donzis) is the use of water insoluble β-(1,3) glucans, which have been obtained from the cell walls of yeasts, for revitalisation of the skin.
Also known from the prior art are very different solutions known for smoothing of the skin and strengthening of the barrier function from a cosmetic or medical view, which only solve a part of the problem and which may have strong side effects. Especially reference is made to the international patent application WO 98/40082 (Henkel), wherein the use of water soluble β-(1,3) glucans as active agents for the skin treatment is described. These glucans, which preferably are schizopyhallan or krestin, i.e. extracts of fungi, have in practice not shown to be sufficiently effective. The complex task of the invention was therefore to provide active agents which could be used against formation of wrinkles in the skin (cosmetic effect) as well as skin diseases such as, for example, cradle cap, psoriasis, seborrheic dermatitis, seborrhea sicca, seborrhea oleosa, psoriasis vulgaris, ichtyoses, UV erythemas, or ulcers as exemplified by diabetes ulcer and aptheous ulcer (medical effect), and which can be both dermatological and toxicological tolerated and which improve the prior art, as described in WO 94/40082